Approximately 1% of children are born with a congenital heart defect, with half requiring medical and/or surgical treatment. Although survival for these children has improved they continue to suffer morbidity and late mortality. This is due to the fact that they are at great risk for developing pulmonary vascular disease. In fact, even early pulmonary endothelial dysfunction, with abnormal vascular reactivity, causes significant morbidity and mortality. Our recent studies, using a lamb model of congenital heart disease and increased pulmonary blood flow, indicate that the development of endothelial dysfunction is associated with derangements in NO signaling. However, the mechanisms by which the endothelial dysfunction occurs have not been adequately resolved. Recently we have found that decreases in NO signaling correlate with altered carnitine metabolism and mitochondrial dysfunction. Thus, the Aims of this proposal are two-fold: 1) To utilize an integrated physiologic, biochemical, cellular, and molecular approach to elucidate the mechanisms underlying the disruption of carnitine metabolism in our lamb model;and 2) To utilize L-carnitine, a compound that has been used for decades to treat inborn errors of metabolism, in a novel and innovative way as a therapeutic agent for the endothelial dysfunction associated with congenital heart disease. Thus, we anticipate that the information garnered from the studies in this exploratory R21 proposal should enable us both to examine the role played by mitochondrial dysfunction in the altered vascular reactivity associated with congenital heart disease and to evaluate L-carnitine as a novel treatment strategy. The incidence of congenital heart defects in the U.S. is ~1 per 100 live births. Approximately 50% of these children require medical and/or surgical attention. The majority of defects requiring treatment are associated with increased pulmonary blood flow. This includes children born with ventricular septal defect, truncus arteriosus, or atrioventricular septal defect. Survival for children born with congenital heart defects has improved because of the development of new diagnostic tools, and advances in surgical techniques and post-operative management. However, these children continue to suffer significant morbidity and late mortality, in part because of abnormal vascular reactivity leading to endothelial dysfunction within the pulmonary circulation. PUBLIC HEALTH RELEVANCE: The factors responsible for the development of endothelial dysfunction are incompletely understood. A better understanding of the cellular and molecular mechanisms that underlie the development of endothelial dysfunction will lead to improved survival for newborns, infants, and children with congenital heart defects. Thus, the studies in this proposal evaluating a compound, L-Carnitine that has been utilized for decades to treat inborn errors of metabolism as a novel and innovative therapy for pulmonary hypertension associated with increased pulmonary blood flow have the potential to significantly impact the survival of children born with congenital heart defects.